Heart failure and atrial fibrillation are common coexisting disease states;data from the Framingham study indicate that heart failure is associated with a 4.5- to 5.9-fold increase in the risk of atrial fibrillation. In patients with advanced heart failure, atrial fibrillation significantly increases the risk of death. Experimental studies have shown that heart failure produces atrial electrophysiologic changes which promote atrial fibrillation;furthermore heart failure induces significant increases in myocardial oxidants. Using a chronic model of nonischemic heart failure, we have preliminary evidence of specific oxidatively-modulated forms of atrial electrophysiologic changes. In this chronic heart failure model, there is a substrate for atrial fibrillation, and in pilot experiments we are able to induce sustained (months) atrial fibrillation. Thus, we can study how both heart failure and atrial fibrillation contribute to the pathogenesis of atrial fibrillation. The purpose of this proposal is to understand the mechanistic bases of atrial fibrillation during heart failure, with a long-term goal of identifying specific targeted therapeutic interventions to effectively prevent or treat atrial fibrillation during heart failure. The central hypothesis of this proposal is that during chronic HF, and chronic HF with superimposed chronic AF, there are specific forms of oxidatively-mediated pathologic atrial remodeling. A combination of in vivo (electrophysiologic and non-invasive imaging techniques) and in vitro (cellular electrophysiology, electron paramagnetic resonance spectroscopy, HPLC analyses, immunohistochemistry and proteomics) techniques will be used to test the central hypothesis, through the following aims. Specific Aim 1 will test the hypothesis that during HF-, and HF with AF-, discrete forms of atrial remodeling occur. Oxidative modulation of atrial myocyte remodeling will be examined. Specific Aim 2 will test the hypothesis that during HF, and HF with AF, specific forms of atrial oxidative stress occur which result in specific alterations in atrial electrophysiology. Specific Aim 3 will test the hypothesis that attenuation of a specific source of oxidative stress will reduce atrial fibrillation and pathologic atrial electrophysiologic remodeling. PUBLIC HEALTH RELEVANCE: Heart failure (resulting from impaired contraction of the heart muscle) and atrial fibrillation (abnormal rhythm of the upper chambers of the heart) are increasingly common causes of disability and death in the U.S. population. Information from this study may result in improved treatments for the prevention and treatment of atrial fibrillation during heart failure.